4-O and 5-aminomethylation of synthetic capsaicin derivatives, a new discovery of capsaicin antagonist

ABSTRACT

A series of 4-O &amp; 5-aminomethylation of synthetic capsaicin derivatives selectively reveal antagonist activity on capsaicin-sensitive sensory neurons, and inhibit its innervating atrium, airway, and ileum smooth muscles in vitro. The compound of this invention has the following formula ##STR1## wherein R is a member selected from the group consisting of ##STR2## wherein R 1  is a member selected from the group consisting of C 1-12  alkyl, C 1-12  alkenyl, C 1-12  alkylene, and C 1-12  alkenylene, and 
     wherein R 2  is a member selected from the group consisting of H, C 1-3  alkylene-NR 1  R 1 , and C 1-6  alkenylene-NR 1  R 1 .

TECHNICAL FIELD OF THE INVENTION

The present invention relates to new and useful capsaicin antagonistderivatives, especially to 4-O & 5-aminomethylation of syntheticcapsaicin derivatives, and other 3-methoxy, 4-hydroxy compounds.

BACKGROUND OF THE INVENTION

Capsaicin is the principle of Capsium annuum Linne, a medicinal plant ofSolanaceae. Capsaicin-sensitive functional change has been found incardia, aorta, trachea, and animal tissues (Maggi & Meli, 1988).Capsaicin has been shown to have potent positive chronotropic andinotropic effects when applied to isolated guinea-pig atria (N. Fukada &M. Fumjiwara et al., J. Pharmacol. 21, 622-24, 1969; J. Molnar et al.,Acta Physiolo. Acad. Sci Hung. 35, 369-74. 1969).

The contraction effect of capsaicin on the isolated guinea-pig ileum wassuggested to be caused by parasympathetic transmission due to SP(substance P) release (L. A. Chahl, Naunyn-schmiedebergs Arch.Pharmacol. 310, 212-15, 1982). Capsaicin has been reported to inhibitneuronal sodium currents (K. Yamanaka et al., Brain Res. 300, 113-9,1984) also inhibit neuronal calcium currents (M. Petersen et al.,Pflvgers Arch. 409, 403-10, 1987). The capsaicin-sensitive effects onthe functions of various tissues, including ileum smooth muscles, cardiamuscles, and airways are known to be caused by the activation of sensoryC-fibres (C. A. Maggi et al., Gen. Pharmacol. 19, 1-43,1988). Thepositive inotropic action of capsaicin is believed to be associated withthe release of CGRP (calcitonin gene-related peptide) from intracardiacneurons, and has shown that capsaicin and CGRP prolong action potentialduration in guinea pig atria (Franco-Cereceda et al., Acta Physiol.Scand. 132, 181-90, 1988).

The effects of capsaicin on rat urethra, urinary bladder,gastrointestinal, renal pelvis, genitourinary tract, and ureters havebeen reviewed by C. A. Maggi, et al.(Gen. Pharmacol. 19, 1-43, 1988).The activation of this proton-gated cation conductance allows sodium,calcium, and potassium ion to flow down its concentration gradient intothe dorsal root ganglion cells causing depolarization and actionpotential generation (C. A. Forbes et al., Soc. Neurosci. Abstract. 14,642. 1988). The inhalation of capsaicin can be used to increase airwayresistance and leads to bronchoconstriction (J. G. Collier et al., Br.J. Pharmacol. 81, 113-7, 1984).

The synthetic capsaicin derivatives with cardioinhibitory andantibronchoconstrictory properties have rarely been described.Capsazepine 2 4-chlorphenyl) ehtylaminothiocarbonyl!-7, 8-dihydroxy-2,3, 4, 5-tetrahydro-1-H-2-benzazepine), first synthesized by Whalloe etal. (Br. J. Pharmacol. 107, 544-552, 1992) as an antagonist of capsaicin(S. Bevan et al., Br. J. Pharmacol. 107, 544-52, 1992), was found to beeffective in inhibiting the contractile response evoked by capsaicin orby electrical field stimulation in guinea-pig bronchi (M. G. Belvisi etal., Eur. J. Pharmacol. 215, 341-344, 1992). Capsazepine, chemicallywith a bicyclic benzazepine moiety similar to the bezodiazepine moietyof diazepam which is effective in inhibiting GABA receptor hypothesizedlocating on preterminal region of capsaicin-sensitive sensory nerves (D.A. Brown et al., Brain Rev. 156, 187-91, 1978), has been evaluated as acompetitive capsaicin antagonist (S. Bevan et al., 1992). Our previousproduct, glyceryl nonivamide, was also proven to be a selectivecapsaicin agonist (I. J. Chen et al., Eur. J. Med. Chem. 27, 187-92,1992). The positive results of S. Bevan et al. (1992) have encouraged usto search for other new capsaicin antagonist.

Previous studies on the structure-activity relationship of nonivamide(N-nonanoyl vanillylamide), the synthetic capsaicin, indicated thatsubstitution for the OH group of capsaicin or nonivamide may lead toless pungency in the capsaicin derivatives (I. J. Chen et al. (1992)),including a non-pungent beta adrenergic blocker derivative withcardiotonic and CGRP releasing properties (I. J. Chen et al., J. Med.Chem. 37, 938-43, 1994). In a similar way, a series of 4-O &5-aminomethylation of capsaicin derivatives (FIG. 1) another bicycliccapsaicin derivative like capsazepine, was first synthesized by achemical reaction both masking the phenolic OH of and bicyclicnonivamide with a series of amino benzyl and amino alkyl compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 Chemical structures of capsaicin and nonivamide

FIGS. 2A-2C Cumulative concentration-response curves to capsaicin (10⁻⁹-10⁻⁵ M) in the absence and presence of CAPBZ and NVABI in the isolatedguinea-pig trachea, expressed as a % of the maximum contraction tocarbachol (1 μM). Each point represents mean±S.E.M of six experiments.

FIGS. 3A-3D Capsaicin (1 μM) caused a positive inotropic andchronotropic response on spontaneously beating guinea-pig right atriumand electrically-driven guinea-pig left atrium. CAPBZ and NVABIpretreatment for 30 min decreased the effect of capsaicin. Each data wasthe mean±S.E.M. of six experiments (*P<0.05. **P<0.01, Student's t-test)

FIG. 4 The effects of CAPBZ on response of guinea-pig ileum to capsaicin(10 μM), substance P (SP, 0.1 μM), and carbachol (0.5 μM). Noteconcentration-dependently reduction of response to SP, and carbachol.Thirty minutes following washout, responses to SP, and carbachol wererecovered.

FIGS. 5A-5B Effect of CAPBZ on the positive chronotropic effects ofincreasing CaCl₂ concentrations in the isolated guinea-pig right atriaand electrically-driven guinea-pig left atria. Each point represents themean of six experiments; vertical bars represent the S.E.M.

FIGS. 6A-6B Effect of CAPCNC6 (10 μM) on the positive chronotropic(spontaneously beating right atrium) and inotropic (electrically-drivenleft atria) effect of increasing Ca²⁺ concentrations in guinea pigs.Beating rate and tension were expressed as % of control values. Datarepresents the mean±S.E.M. (n=7).

FIG. 7 Cumulative concentration-response curves for the chronotropiceffects of hCGRP in the absence and presence of CAPBZ (50 μM) andbenzocaine (10 μM) on spontaneous beatings of guinea-pig right atria.Each value is the mean±S.E.M. of six experiments.

FIGS. 8A-8C Percentage of inhibition of capsaicin (10 μg/kg, i.v.)induced triphasic response during a 15 min infusion of capsazepine orNVABI or NVADA (100 μg/kg/min) and recovery from A, B and C phase ofblood pressure after termination of each infusion. Each data was themean±S.E.M. of six experiments.

DETAILED DESCRIPTION

The present invention describes a series of 4-O & 5-aminomethylatedcapsaicin derivatives which have the formula A: ##STR3## Wherein R is##STR4## R₂ represents H, C₁₋₆ --NR₁ R₁. I. Methods of Preparation

The methods of preparation for this invention (formula A) was shown inthe section of Synthesis and Its Scheme (IV) in Schemes 1-4. The methodsmight be performed using amino benzyl, amino alkyl, amino phenylaceticacid, 4-aminopropiophenone and anthranilic acid compound and theiresters to react with N-nonanoylvanillylamide (NVA) or other substitutedguaiacol compounds via the Mannich reaction to give 4-O- and5-amino-methylated derivatives of capsaicin or other guaiacol compounds(Formula A and FIG. 1).

The other methods of preparation comprise reacting NVA(N-nonanoylvanillylamide) or other guaiacol derivatives withdialkylamine to give 4-guaiacolic and 5-aminomethylated compounds (e.g.Compound 4, Scheme 4) via Mannich reaction as described shown in FormulaA and Scheme of Synthesis Section (IV), Schemes 1-4.

In the invention of novel capsaicin derivative compounds most of thereacting materials were first amine, second amine, and/or substitutedwith straight or branched alkyl, straight or branched alkenyl. Theguaiacoxyl group compounds including 4-O- and 5-aminoethylated capsaicin(CAP) nonvamide and other guaiacol derivatives were substituted withstraight or branched alkyl group, alkenyl group. These structures ofcompounds of formula A described above were assigned according to the ¹H-NMR, IR, MS, elemental analytical data, ¹³ C-NMR.

II. Pharmacological Activity

A. Antagonist activity of compounds on capsaicin-induced contractilityof isolated guinea-pig bronchi and trachea

Adult guinea pigs (Hartley), weighing 350-450 g, were sacrificed by ablow on the head followed by cervical dislocation. The bronchi andtrachea were removed from the lungs, cleaned of all parenchyma, andimmediately placed in Kreb's solution. As the method reported by M. G.Belvisi et al. (Eur. J. Pharmacol. 215, 341-4, 1992).

Cumulative addition of 0.01-30 μM capsaicin to the organ bath caused aconcentration-dependent increase in contraction of isolated guinea-pigbronchi and trachea. These effects were shifted rightward in bronchi inthe presence of compound 1 (CAPBZ, 1.0-100, μM)), compound 3 (CAPBI,1.0-100 μM) and capsazepine (1-10 μM). This inhibitory effect ofcompound 1 and 3 were more effective in bronchi than in trachea (FIGS.2A-C).

B. Antagonist activity of compound on capsaicin-induced contraction inthe isolated guinea-pig atrium

Also as shown in FIGS. 3A-3D, 1.0 μM capsaicin induced a positiveinotropic and chronotropic effect in the isolated right and leftguinea-pig atria, respectively. These effects were significantlyinhibited in the presence of 0.1-10 μM compound 1 (CAPBZ), compound 6(CAPCNC6), compound 11 (NVABI), compound 12 (NVADA),concentrationdependently. The IC₅₀ value against capsaicin-inducedcontractility for these compounds can be estimated from the datapresented in FIGS. 3A-3D.

C. Antagonist activity of compound on capsaicin and substance Pinducedcontractilities of isolated guinea-pig ileum

The abdominal incisions for the guinea pig were made and ilea wereisolated and placed in cold (4° C.) Tyrode's solution. 2.5 cm segmentsof ileum were then trimmed and suspended in an organ bath containing 20ml low calcium Kreb's solution, aerated with 95% O₂ and 5% CO₂ at 37° C.As the method reported by M. Takaki et al. (Eur. J. Pharmacol. 174,5762, 1989).

As shown in FIG. 4, carbachol was used as a control agent to inducemaximum contraction of ileum smooth muscle; 10 μM capsaicin and 0.1 μMsubstance P (SP) induced weaker contractions. This effect of capsaicinor substance P was inhibited in the presence of 1.0-100 μM of compound 1(CAPBZ), concentration-dependently.

D. Effects of compound on the calcium channel in the isolated guinea-pigatrium

Cumulative addition of CaCl₂ concentrations in the Kreb's solution couldconcentration-dependently produce a positive chronotropic effect in theisolated spontaneously beating right atrium, and a positive inotropiceffect in the isolated electrically driven left guinea-pig atrium.Pretreatment with compound 1 and 6 could inhibit these calcium effects(FIGS. 5A-5B and FIGS. 6A-6B).

E. Ineffective effect on CGRP releasing in the isolated atrium

Cumulative addition of hCGRP to the organ bath concentrationdependentlyincreased the beating in the right atrium and the tension in theelectrically driven left atrium of the guinea pig. These effects werenot inhibited by compound 1 (CAPBZ). After the pretreatment with CGRPfor 30 minutes, compound 1 also could not change CGRP-inducedcontractilities (FIG. 7).

F. Effects of compounds on capsaicin-induced blood pressure and heartrate changes

After 15 minutes, intravenous perfusion of NVABI, NVABZ, NVADA andcapsazepine (100 μg/kg/min), bolus capsaicin (10 μg/kg, i.v.) was givenat 5th, 10th, 15th, 30th, 45th and 60th minutes in thepentobarbital-anesthesized Wistar rats. This experiment was carried outto study the antagonistic effects of these compounds on capsaicin elicittriphasic response of blood pressure. The results indicated theantagonist activities of NVABI, NVABZ, and capsazepine were recovered tobasal level by saline infusion for 30, 45, and 60 minutes gradually.Estimated recovery half life of capsaicin-induced blood pressure changes(A, B, and C effect) for NVABI was 10.67, 4.30, and 21.75 min, for NVABZ55.13 min, for NVADA 4.30, 9.01, and 4.49, and for capsazepine 2.73,2.89, and 3.78 min (Table 1 & 2). The duration order of their antagonistactivities was NVABZ>NVABI>capsazepine. The efficacy order of theirantagonist activities was capsazepine>NVABZ>NVABI in the A effect,NVABI>capsazepine>NVABZ in the B effect, and capsazepine>NVABI>NVABZ inthe C effect. These compounds could not inhibit calcitonin gene-relatedpeptide, substance P, and bradykinininduced hypotensive effects.Intrathecal perfusion of these compounds also reversed epigastricintraarterial capsaicin (10 μg/kg)-induced hypotensive reflex in rats(Table 3). It is concluded that NVABI, NVABZ, NVADA, and capsazepine allmodulate the presynaptic capsaicin-sensitive sensory neurons and thusmay inhibit capsaicin-induced release of neuropeptides, but aredifferent from each other in their pharmacokinetic properties.

III. Pharmaceutical Compositions

The novel compounds of this invention together with a conventionaladjuvant, carrier, or diluent, and if desired in the form ofpharmaceutically acceptable salts, may be prepared in the form ofpharmaceutical compositions and unit dosages. In such forms, they may beemployed as solids, or liquids, for oral use; in the form ofsuppositories for rectal administration; in the form of sterileinjectable solutions for parental (including subcutaneous) use.

The solid pharmaceutical dosages may comprise disintegrating agents suchas starch, sodium carboxymethylcellulose, and/or binders such as ethylalcohol, glycerin, and/or carriers such as magnesium stearate, lactose,which are prepared by conventional pharmaceutical methods. The sterileinjectable solutions, dosages, or other liquid preparations can beadjusted with buffers, such as phosphate solutions, if desired, withauxiliary agents, emulsifiers, which particularly comprise aqueoussolutions or salt solutions of the novel compounds. The novelpharmaceutical compositions and unit dosages thereof allow the formationof a pharmaceutically acceptable salt, are extremely useful inselectively antagonizing capsaicin-sensitive sensory neurons, inhibitinginnervation of the atrium, airway and ileum smooth muscles in vitro, andas well as producing direct cardioinhibitory effects, tachyphylaxis. Thenovel compounds of the invention may accordingly be administered to asubject, e.g. a living animal body, including a human, and should beadjusted according to the complexity of the symptoms.

IV. Synthesis and its Scheme

EXAMPLE 1

N P-(carboxylic acid ethyl ester) phenylamine-(4-oxymethylene,5-methylene)-3-methoxybenzyl! nonanamide, capsazocaine, (compound 1)

10 g nonivamide was dissolved in a mixture of absolute methanol 20 ml,mixed with 5.7 g benzocaine in 10 ml absolute methanol solution, thenpoured into a three-neck flask, adding 10 ml 34-37% formaldehydesolution, 5 ml acetic acid, then refluxing under 70°-75° C. for 24 hrs.After cooling, the solvent was evaporated. The residue wasrecrystallized from ethylacetate to give compound 1, Yield 77%.

EXAMPLE 2

N Ethylamino-(4-oxymethylene 5-methylene)-3-methyoxybenzyl! nonanamide(compound 2)

10 g nonivamide was dissolved in 1000 ml ethanol, added to 3.5 moletimes ethylamine, 4 mole times formaldehyde, and drops of acetic acid,then refluxed under room temperature for 24 hrs. After cooling, thesolvent was evaporated. The residue was recrystallized from n-hexane togive compound 2.

EXAMPLE 3

N-hexylamino-(4-oxymethene, 5-methylene)-3-methoxybenzyl! nonanamide(compound 6)

10 g nonivamide and 5 ml hexylamine was used as the starting materialand treated according to the procedure described in example 1 to givecompound 6.

EXAMPLES 4-12

The compounds 3-5, 7-12 can be prepared in a manner analogous to thosedescribed in example 1-3. The physical constants and spectral data areshown in Section IV. ##STR5## V. Pharmaceutical Formulation

A typical tablet which may be prepared by conventional tablettingtechniques contains

    ______________________________________                                        active compound        40 mg                                                  lactose                30 mg                                                  starch                  8 mg                                                  mag.stearate           10 mg                                                  corn starch            12 mg                                                  ______________________________________                                    

VI. Physical Constants and Spectral Data of Synthesized Examples

The physical constants and spectral data are shown as follows:

Compound 1

N P-(carboxylic acid ethyl ester)-phenylamine-(4-oxymethylene,5-methylene)-3-methoxybenzyl! nonanamide, capsazocaine, (compound 1)

mp: 145°-147.5° C.,

1H-NMR(CDCl₃):

δ 0.87 (t, 3H, CH₃),

1.32-2.20 (m, --(CH₂)×7),

3.84 (s, 3H, OCH₃),

4.32 (q, 2H, --COO--CH₂ CH₃),

4.32 (d, 2H, ArCH₂ --NHCO--),

4.65 (S, 2H, ArCH₂ --N═),

5.45 (S, 2H, ArOCH₂ ═N--),

5.71 (m, 1H, NH),

6.57 (d, 1H, Ar),

6.66 (d, 1H, Ar),

7.08 (m, 2H, Ar--COO--),

7.94 (m, 2H, Ar--N);

IR(KBr) υ (cm⁻¹)

1650 cm⁻¹ (C═O),

1720 cm⁻¹ (--COOR)

3300 cm⁻¹ (NH--CO--);

MS(FAB+):MS m/z 483(M+H)+ (FIGS. 5A-5B);

Anal. Calcd for C₂₈ H₃₈ N₂ O₅ ;

C, 69.57%, H, 7.88%, N, 5.80%, O, 16.75%,

Found:

C, 69.53%, H, 7.90%, N, 5.75%, O, 6.82%,

UV(EtOH) λ max nm (log ε): (FIGS. 6A-6B) 211 (2.45), 289 (2.36)

Compound 2

N Ethylamino-(4-oxymethylene, 5-methylene)-3-methyoxybenzyl! nonanamide(compound 2)

mp: 94°-97° C.

¹ H-NMR; (CDCl₃) (FIGS. 3A-3D):

δ 0.87 (t, 3H, CH₃),

1.3-1.61 (m, CH₂),

2.21 (t, 2H, J=7.58, NH--CO--CH₂),

2.83 (tert, 2H, J=10.71, N--CH₂),

3.85 (s, 3H, OCH₃),

3.98 (s, 2H, Ar--CH₂),

4.32 (d, 2H, J=2.84, Ar--CH₂ --N),

4.95 (s, 2H,O--CH₂ --N),

5.63 (s, 1H, NH),

6.65-6.66 (d, 2H, Ar--H);

IR(KBr) υ (cm⁻¹)

1650 cm⁻¹ (C═O),

3300 cm⁻¹ (NH) (FIG. 4);

V (EtOH) λ max nm (log ε):

7.33

(FAB-MS) M/Z: 362 (FIGS. 6A-6B)

Compound 3

N-Allylamino-(4-oxymethylene, 5-methylene)-3-methoxybenzyl! nonanamide

1H-NMR (CDCl₃):

60.87 (t, 3H, CH₃),

1.2-2.25 (m, 14H, 7×CH₂),

3.40 (d, 2H, ═NCH₂),

3.86 (s, 3H, OCH₃),

3.98 (s, 2H, ArCH₂ N═),

4.32 (d, 2H, ArCH₂ NHCO),

4.94 (s, 2H, OCH₂ N═),

5.15-5.28(m, 1H, C═CH--),

5.63 (b, 1H, NH),

5.80-5.95 (m, 1H, H--C═C),

6.48 (d, 1H, Ar--H),

6.67 (d, 1H, Ar--H).

Compound 4

N-diethylamino-(4-oxymethylene, 5-methylene)-3-methoxy, benzyl!nonanamide

1H-NMR (CDCl₃):

δ 0.8-0.9 (t, 3H, CH₃),

0.98-1.05 (t, 3H, CH₃),

1.10-1.20 (t, 3H, CH₃),

1.20-2.17 (m, 14H, 7×CH₂),

2.48-2.60 (q, 2H, ═NCH₂),

2.79-2.91 (q, 2H, ═NCH₂),

3.67 (s, 2H, Ar--CH₂ N),

3.72 (s, 3H, OCH₃),

4.12 (d, 2H, ArCH₂ NHCO),

6.54 (s, 1H, Ar--H),

6.73 (s, 1H, Ar--H),

8.24 (b, 1H, NH).

Compound 5

N-tetramethyleneamino-(4-oxymethylene, 5-methylene)-3-methoxybenzyl!nonanamide

M+!: 376

1H-NMR (CDCl₃):

δ 0.8-0.9 (t, 3H, CH₃),

1.15-2.60 (m, 22H, 11×CH₂),

3.68 (s, 2H, Ar--CH₂ N),

3.72 (s, 3H, OCH₃),

4.13 (d, 2H, ArCH₂ NHCO),

6.55 (s, 1H, Ar--H),

6.73 (s, 1H, Ar--H),

8.16 (b, 1H, NH).

Compound 6

N- hexylamino-(4-oxymethene, 5-methylene)-3-methoxybenzyl! nonanamide(compound 6)

mp: 107.5°-108.5° C.,

1H-NMR(CDCl₃):

δ 0.87 (t, 6H, CH₃),

1.28 (s, 16H, CH₂),

1.60 (m, 4H, CH₂),

2.21 (t, 2H, J=7.51 Hz, CO--CH),

2.74 (t, 2H, J=7.35 Hz, N--CH₂),

3.85 (s, 3H, OCH₃),

3.96 (s, 2H, Ar--CH₂ --NH),

4.32 (d, 2H, J=5.68 Hz, Ar--CH₂ --NH),

4.93 (s, 2H, O--CH₂ --N),

5.72 (t, 1H, NH),

6.49 (d, 1H, J=1.64 Hz, Aromatic-H),

6.65 (d, 1H, J=1.44 Hz, Aromatic-H)

¹³ C-NMR(CDCl₃):

δ 14.1 (CH₃),

22.6, 25.8, 26.9, 28.1, 29.2, 29.3, 31.7 & 31.8 (aliphatic CH₂),

36.9 (CO--CH₂),

43.5 (Ar--CH₂ --NH),

50.0 (Ar--CH₂ --NH)

51.5 (N--CH₂),

55.9 (OCH₃),

82.9 (O--CH₂ --N),

109.2, 118.7, 120.7, 130.0, 143.0 & 147.8 (Ar--C)

172.9 (C═O)

IR (HBr) υ max:

3300 cm⁻¹ (N--H)

2920 & 2840 cm⁻¹ (CH₂)

1640 cm⁻¹ (C--O)

1540, 1490, 1220, 1150 & 920 cm⁻¹

UV (C₂ H₅ OH) λ max (log ε):

285 (3.346), 216 (4.335) nm

Anal. Calcd for C₂₅ H₄₂ O₃ N₂

N 6.65%; C 71.28%; H 10.07%

MS (FAB+):

M/Z 419 (M+H)+ 418

MSHRFAB 418.3278

Compound 7

p-acetic acid ethylester-benzylamino-(4-oxymethylene,5-methylene)-3-methoxybenzyl! nonanamide

1H-NMR (CDCl₃):

0.83-0.90 (t, 3H, CH₃)

1.03-2.22 (s, 14H, CH₂ ×7)

3.51 (s, 2H, ArCH₂ COOC₂ H₅)

3.83 (s, 3H, OCH₃)

4.06-4.18 (q, 2H, COOCH₂ CH₃)

4.29-4.32 (d, 2H, ArCH₂ NHCO)

4.58 (s, 2H, ArCH₂ N═)

5.41 (s, 2H, ArOCH₂ N═)

5.62 (b, 1H, NH)

6.52 (d, 1H, ArH)

6.63 (d, 1H, ArH)

7.05-7.20 (m, 4H, 4×ArH)

Compound 8

p-carboxylyl acid-benzylamino-(4-oxymethylene,5-methylene)-3-methoxybenzyl! nonanamide

1H-NMR (CDCl₃):

0.81-0.87 (t, 3H, CH₃)

1.23-2.14 (m, 14H, CH₂ ×7)

3.69 (s, 3H, OCH₃)

4.13-4.15 (d, 2H, ArCH₂ NHCO)

4.69 (s, 2H, ArCH₂ N═)

5.48 (s, 2H, ArOCH₂ N═)

6.58-6.70 (q, 2H, ArH)

7.16-7.20 (d, 2H, ArCOO)

7.78-7.82 (d, 2H, ArCOO)

8.14-8.19 (t, 1H, CH₂ NHCO)

12.44 (s, 1H, ArCOOH).

Compound 9

N o-(carboxylic acid methylester)-phenylamino-(4-oxymethylene,5-methylene)-3-methoxybenzyl! nonamide

1H-NMR (CDCl₃):

0.87 (t, 3H, CH₃)

1.10-2.20 (m, 14H, CH₂ ×7)

3.73 (s, 3H, COOCH₃)

3.84-3.87 (d, 3H, OCH₃)

4.30 (d, 2H, ArCH₂ NHCO)

4.42 (s, 2H, ArCH₂ N═)

5.70 (b 1H, NH)

6.74 (m, 2H, 2×ArH)

7.08-7.10 (d, 1H, ArH)

7.13-7.14 (d, 12H, ArH)

7.74-7.75 (d, 2H, ArH)

Compound 10

N p-carboxylic acid isobutylester-phenylamino-(4-oxymethylene,5-methylene)-3-methoxybenzyl! nonamide

mp: 110-110.5 C.

1H-NMR (CDCl₃):

δ 0.87 (t, 3H, CH₃)

δ 1.27 (m, 12H, (CH₂)6 CH₃)

δ 2.18 (d, 2H, --CO--CH₂ --, J=8.2 Hz)

δ 3.84 (s, 3H, OCH₃)

δ 4.05 (d, 2H, COOCH₂ CH₃, J=6.6 Hz)

δ 4.34 (d, 2H, --ArCH₂ NH--, J=5.7 Hz)

δ 4.67 (s, 1H, N--H)

δ 6.62 (d, 1H, Ar--H, J=3.4 Hz)

δ 7.09 (d, 2H, Ar--H--COO--, J=9.1 Hz)

δ 7.96 (d, 2H, ArH, J=9.0 Hz)

IR (KBr) (cm⁻¹)

1650 (CO)

1720 (COOR)

3300 (NH)

MS(FAB+): MS m/z 510 (M+H)

Anal. Calcd. for C₃₀ H₄₂ N₂ O₅

Found:

C, 70.18%, H, 8.25%, N, 5.65%

Compound 11

N- (4-hydroxy, 5-diethylaminomethyl)-3-methyoxybenzyl! nonamide

mp: 218-218.5 C.

1H-NMR (CDCl₃)

δ 0.87 (t, 3H, CH₃, J=6.2 Hz)

δ 1.24 (m, 12H, (CH₂)₆ CH₃)

δ 2.12 (t, 2H, --NHCOCH₂ --, J=7.3 Hz)

δ 2.83 (m, 2H, NCH₂ --)

δ 3.72 (s, 3H, OCH₃)

δ 4.14 (d, 2H, Ar--CH₂ --, J=5.8 Hz)

δ 6.54 (d, 1H, Ar--H, J=1.7 Hz)

IR(KBr) (cm⁻¹)

1650 cm⁻¹ (CO)

2950 cm⁻¹ (CH)

MS (FAB+):MS m/z 378 (M+H)+

Anal. Calcd for C₂₂ H₃₈ N₂ O₃

Compound 12

N p-ethylketone-phenylamino-(4-oxymethylene,5-methylene)-3-methoxybenzyl! nonamide

Melting point: 124°-126° C.

NMR

δ 0.87 (3H, t, CH₃ --(CH₂)₇ --)

1.256 (3H, t, CH₃ --CH₂ CO--)

1.25-1.33 (12H, m, 6×(CH₂)₆)

2.20 (2H, t, CO--CH₂ --)

2.92 (2H, q, CH₃ CH₂ CO)

3.85 (3H, s, OCH₃)

4.68, 5.47 (each 2H, s, --CH₂ --N--CH₂ --O--)

5.65 (1H, t, --CH₂ --NHCO--)

6.58 (1H, s, 3--H)

6.67 (1H, s, 5--H)

7.10 (2H, d, 2' and 6'--H)

7.91 (2H,d, 3'and 5'--H)

                  TABLE 1                                                         ______________________________________                                        Recovery half-life of capsaicin-induced blood                                 pressure (A, B and C phase) changes during a 15 min                           infusion of NVABI, NVADA or capsazepine                                                t.sub.1/2  (min.)*                                                   Compd.     A phase      B phase C phase                                       ______________________________________                                        NVABI      10.67        15.75   21.75                                         NVADA      4.30         9.00    4.49                                          Capsazepine                                                                              2.73         2.89    3.78                                          ______________________________________                                         *t.sub.1/2  was calculated by one compartment model.                     

                  TABLE 2                                                         ______________________________________                                        Recovery half-life of capsaicin-induced heart rate changes                    (fast and slow phase) during a 15 min infusion of NVABI,                      NVADA or capsazepine.                                                                      t.sub.1/2  (min)*                                                Compd.         Fast phase                                                                             Slow phase                                            ______________________________________                                        NVABI          11.95    15.75                                                 NVADA          5.33     6.00                                                  Capsazepine    1.36     3/52                                                  ______________________________________                                         *t.sub.1/2  was calculated by one compartment model.                     

                  TABLE 3                                                         ______________________________________                                        Effects of intrathecal infusion (i.t.) of 1 nmole of NVABI,                   NVADA or capsazepine on the depressor reflex responses to                     intraarterial injection of capsaicin (10 μg/kg) induced blood              pressure changes.                                                             Pretreatment (i.t. 1 nmole)                                                                    Capsaicin (i.a., 10 μg/kg)                                ______________________________________                                        None             -19.6 ± 1.9                                               NVABI            19.2 ± 2.5*                                               NVADA            -10.6 ± 2.5                                               Capsazepine      25.8 ± 3.0*                                               ______________________________________                                    

All values after pretreatment differ significantly (* P<0.05) fromcontrol. Each datum represents the mean±S.E.M. (n=6)

What we claim is:
 1. A capsaicin derivative having the formula ##STR6##wherein R is a member selected from the group consisting of --R₁##STR7## wherein R₁ is a member selected from the group consisting ofC₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkylene, and C₁₋₁₂ alkenylene,andwherein R₂ is a member selected from the group consisting of H, C₁₋₃alkylene-NR₁ R₁, and C₁₋₆ alkenylene-NR₁ R₁.
 2. The capsaicin derivativeas defined in claim 1wherein R₁ is selected from the group consisting ofC₁₋₈ alkyl, C₁₋₈ alkenyl, C₁₋₈ alkylene, and C₁₋₈ alkenylene, andwherein R₂ is selected from the group consisting of H, C₁₋₃ alkylene-NR₁R₁, and C₁₋₃ alkenylene-NR₁ R₁.
 3. The capsaicin derivative as definedin claim 1wherein R₁ is selected from the group consisting of C₁₋₆alkyl, C₁₋₆ alkenyl, C₁₋₆ alkylene, and C₁₋₆ alkenylene.
 4. The compoundas defined in claim 1 whereinR₁ and R₂ are straight-chained or branched.5. A pharmaceutical salt prepared from the compound as defined inclaim
 1. 6. A pharmaceutical composition comprising a compound havingthe following formula ##STR8## wherein R is selected from the groupconsisting of --R₁ ##STR9## wherein R₁ is selected from the groupconsisting of C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkylene, and C₁₋₁₂alkenylene, andwherein R₂ is selected from the group consisting of H,C₁₋₆ alkylene-NR₁ R₁ and C₁₋₆ alkenylene-NR₁ R₁, and wherein saidcomposition contains an amount of said compound sufficient toselectively antagonize capsaicin-sensitive sensory neurons of a livinganimal body.
 7. A pharmaceutical composition comprising a compoundhaving the following formula ##STR10## wherein R is selected from thegroup consisting of --R₁ ##STR11## wherein R₁ is selected from the groupconsisting of C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkylene, and C₁₋₁₂alkenylene, andwherein R₂ is selected from the group consisting of H,C₁₋₆ alkylene-N₁ R₁, and C₁₋₆ alkenylene-NR₁ R₁, and wherein saidcomposition contains an amount of said compound sufficient to inhibitinnervation of an airway in a living animal body.
 8. A pharmaceuticalcomposition comprising a compound having the following formula ##STR12##wherein R is selected from the group consisting of --R₁ ##STR13##wherein R₁ is selected from the group consisting of C₁₋₁₂ alkyl, C₁₋₁₂alkenyl, C₁₋₁₂ alkylene, and C₁₋₁₂ alkenylene, andwherein R₂ is selectedfrom the group consisting of H, C₁₋₆ alkylene-NR₁ R₁, and C₁₋₆alkenylene-NR₁ R₁, and wherein said composition contains an amount ofsaid compound sufficient to inhibit innervation of the ileum smoothmuscles of a living animal body.
 9. A pharmaceutical compositioncomprising a compound having the following formula ##STR14## wherein Ris selected from the group consisting of --R₁ ##STR15## wherein R₁ isselected from the group consisting of C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂alkylene, and C₁₋₁₂ alkenylene, andwherein R₂ is selected from the groupconsisting of H, C₁₋₆ alkylene-NR₁ R₁, and C₁₋₆ alkenylene-NR₁ R₁, andwherein said composition contains an amount of said compound sufficientto produce direct negative chronotropic and/or negative inotropiccardioinhibitory effects.
 10. A pharmaceutical composition comprising acompound having the following formula ##STR16## wherein R is selectedfrom the group consisting of --R₁ ##STR17## wherein R₁ is selected fromthe group consisting of C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkylene, andC₁₋₁₂ alkenylene, andwherein R₂ is selected from the group consisting ofH, C₁₋₆ alkylene-NR₁ R₁, and C₁₋₆ alkenylene-NR₁ R₁, and wherein saidcomposition contains an amount of said compound sufficient to producetachyphylaxis.